The primary goals of the proposed research are the development of animal models which will allow us to predict accurately whether or not a compound is likely to be effective in the treatment of schizophrenia and, if so, whether it has the potential to induce tardive dyskinesia (TD) after long-term treatment. The models proposed are based on a chronic approach to electrical self-stimulation (SS) of the brain in rats. We determine the effects of chronic, systemic administration of antipsychotic agents on animals self-stimulating to electrodes in different dopamine-containing areas of the brain. A profile based on the information obtained from each brain site tested is then compiled. This includes: 1) whether a compound has acute or delayed suppressive effects on bar-press rates when our electrode is in a particular location; 2) whether tolerance develops to the suppressive influence of the antipsychotic; 3) whether the attenuation of bar-pressing is reversible by anticholinergic agents; and 4) whether there is a withdrawal-related increase in bar-pressing over control levels once the antipsychotic is discontinued. Based on these profiles, our results to date indicate that the SS pattern obtained from points along the trajectory of the nigrostriatal dopamine pathway mimics the extrapyramidal side-effect pattern obtained with most antipsychotic agents. In marked contrast to these effect, SS from the nucleus accumbens (NAcc, a terminal region of the mesolimbic dopamine pathway) parallels the pharmacotherapy of schizophrenia.